Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens

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• 作者：Tiffany C. Scharschmidt ; Mao-Qiang Man ; Yutaka Hatano ; Debra Crumrine ; Roshan Gunathilake ; John P. Sundberg ; Kathleen A. Silva ; Theodora M. Mauro ; Melanie Hupe ; Soyun Cho ; Yan Wu ; Anna Celli ; Matthias Schmuth ; Kenneth R. Feingold ; Peter M. Elias
• 关键词：Atopic dermatitis ; barrier function ; contact dermatitis ; filaggrin ; flaky-tail mouse ; lamellar body
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2009
• 出版时间：September 2009
• 年：2009
• 卷：124
• 期：3
• 页码：496-506.e6
• 全文大小：3550 K

文摘

Background

Mutations in the human filaggrin gene (FLG) are associated with atopic dermatitis (AD) and are presumed to provoke a barrier abnormality. Yet additional acquired stressors might be necessary because the same mutations can result in a noninflammatory disorder, ichthyosis vulgaris.

Objective

We examined here whether FLG deficiency alone suffices to produce a barrier abnormality, the basis for the putative abnormality, and its proinflammatory consequences.

Methods

By using the flaky-tail mouse, which lacks processed murine filaggrin because of a frameshift mutation in the gene encoding profilaggrin that mimics some mutations in human AD, we assessed whether FLG deficiency provokes a barrier abnormality, further localized the defect, identified its subcellular basis, and assessed thresholds to irritant- and hapten-induced dermatitis.

Results

Flaky-tail mice exhibit low-grade inflammation with increased bidirectional, paracellular permeability of water-soluble xenobiotes caused by impaired lamellar body secretion and altered stratum corneum extracellular membranes. This barrier abnormality correlates with reduced inflammatory thresholds to both topical irritants and haptens. Moreover, when exposed repeatedly to topical haptens at doses that produce no inflammation in wild-type mice, flaky-tail mice experience a severe AD-like dermatosis with a further deterioration in barrier function and features of a T_H2 immunophenotype (increased CRTH levels plus inflammation, increased serum IgE levels, and reduced antimicrobial peptide [mBD3] expression).

Conclusions

FLG deficiency alone provokes a paracellular barrier abnormality in mice that reduces inflammatory thresholds to topical irritants/haptens, likely accounting for enhanced antigen penetration in FLG-associated AD.